SIDE CHAIN FLUORO SUBSTITUTED 3-CARBOXYSTEROIDS

Abstract: The present invention provides compounds of formula (I) wherein A, R1, R2, R3 and Z are defined in the description. The compounds of formula (I) are testosterone 5 alpha -reductase inhibitors and are therapeutically useful in the treatment of e.g., benign prostatic hyperplasia, prostatic and breast cancers, seborrhoea, female hirsutism and male pattern baldness.

Description: SIDE CHAIN FLUORO SUBSTITUTED 3-CARBOXYSTEROIDS The present invention relates to novel 3-carboxysteroids fluorosubstituted in the side chain, to a process for their preparation, to pharmaceutical compositions containing them and to the use of said compounds as inhibitors of androgen action, by means of testosterone 5α-reductase inhibition. In certain androgen responsive tissues the action of testosterone is mediated primarily through its 5α- reduced metabolite, dihydrotestosterone (DHT) (Bruchowsky N., Wilson J.D.; J. Biol. Chem. 243, 5953, 1968) . The conversion of testosterone to dihydro¬ testosterone is catalysed by the enzyme 5 -reductase and if 5 -reductase is inhibited, the formation of dihydro¬ testosterone is reduced and its specific androgenic effect is attenuated or prevented. The 5α-reductase inhibitors may find medical application for the treatment of hyperandrogenic conditions, e.g. certain prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer, and certain skin-hair conditions, such as acne, seborrhoea, female ' hirsutism and male pattern baldness (Siiteri P.K., Wilson J.D., J. Clin. Invest. .49 . , 1737, 1970; Price V.H., Arch. Dermatol, III. 1496, 1975; Sandberg A.A. , Urology 17. 34, 1981) . Also breast cancer treatment can take advantage from use of 5α-reductase inhibitors as the said tumour is known to be aggravated by presence of androgens. Androst-4-en-3-one-17β-carboxylic acid and its methyl ester (Voigt and Hsia, Endocrinology, 92. 1216 (1973); Canadian Patent No. 970,692) are among the first steroidic compounds described as 5c--reductase inhibitors. Two 5, 10-secosteroids having a 3-keto-4,5-diene system in the expanded ring have been found to be selective inhibitors of rat epididy al 5α-reductase (Robaire et al., J. Steroid Biochem. 8 . , 307-310 (1977)) . The (20R) -4-diazo-21-hydroxy-20-methyl-5α-pregnan-3-one and its analogs are reported to be enzyme activated inhibitors of testosterone 5 -reductase (Blohm et al., Biochem. Biophys. Res. Comm. <35_, 273-80 (1980) ; United States Patent 4,317,817). Another series of enzyme-directed irreversible in¬ hibitors of 5α-reductase have been prepared by introducing a 6-methylene moiety into substrates type 3- keto-Δ 4 -progestins and androgens (Petrow et al., Steroids 38. 352-53 (1981) ; United States Patent 4,396,615)) . More recently unsaturated derivatives of 3-carboxy steroids have been reported as uncompetitive 5α- reductase inhibitors versus testosterone (Biorg. Chem. 12, 372-376 (1989) ; Eur. Pat. Appln. no. 0289327 and Eur. Pat. Appln. no. 0567271 A2) . 4-Aza steroids are by far the most studied steroid 5α- reductase inhibitors. The compounds known in the art are reported in a very large number of publications and patents. In particular the 17β-acylamides and their metabolites are described in: J. Med. Chem. 27 ./ 1690- 1701 (1984) , J. Med. Chem. 29, 2298-2315 (1986), Eur. Pat. Appln. No. 0004949; US patent No. 4,377,584; Eur. Pat. Appln. 0155096; US patent 4,845,104; Eur. Pat. Appln. 0462662; Eur. Pat. Appln. 0,484094 A2; US Patent 4,859,681; WO 91/12261. The invention provides compounds of the following formula (I) wherein A is a single bond or a straight or branched C,-C 6 alkylene chain; R- is a hydrogen atom or a C,-C 6 alkyl group optionally, substituted by one or more fluorine atoms; R 2 is: a) a C,-C 6 alkyl group optionally substituted by one or more substituents chosen among fluoro, Cj-C 4 alkoxycarbonyl, carbamoyl, carboxy, hydroxy, C,-C 4 alkoxy, amino, di-C^ , alkylamino, mercapto and C,- C 4 alkylthio; or b) a C 5 -C 7 cycloalkyl or a C 6 -C 10 cycloalkylalkyl group optionally substituted by one or more fluorine atoms; or c) an aryl or a C 7 -C 10 arylalkyl group, either unsub¬ stituted or ring substituted by one or more substituents chosen among halogen, C,-C 4 alkyl, C,- C 4 alkoxy, hydroxy and trifluoromethyl; or d) a C 6 -C 10 heterocyclylalkyl group in which the heterocyclic ring contains one or more heteroatoms chosen among N, O and S and is either unsubstituted or ring substituted by one or more fluorine atoms; R 3 is hydrogen, a C,-C 4 alkyl group or an aryl or a C 7 - C 10 arylalkyl group, either unsubstituted or ring substituted by one or more substituents chosen among halogen, C,-C 4 alkyl, C,-C 4 alkoxy, hydroxy and tri- fluoromethyl; Z is: a') a C,-C 6 alkyl group optionally substituted by one or more fluorine atoms; b') an -0R 5 group wherein R 5 is a C,-C 6 alkyl group; C) a group wherein each of R 6 and R 7 , indepen- dently, is hydrogen, C,-C 6 alkyl, C 5 -C 7 cycloalkyl or phenyl, or R 6 and R 7 , taken together with the nitrogen to which they are linked, form a pentatomic or hexatomic saturated heteromono- cyclic ring, optionally containing at least one additional heteroatom selected from oxygen and nitrogen; provided that when Z is a group OR 5 as defined above under b') R 2 is a) a C,-C 6 alkyl group substituted by one or more substituents chosen among fluoro, C,-C 4 alkoxycarbonyl, carbamoyl, carboxy, C,-C 4 alkoxy, a ino, di-C,-C 4 alkylamino, mercapto and C,-C 4 alkylthio or b) a C 5 -C 7 cycloalkyl or a C 6 -C 10 cycloalkylalkyl group, unsubstituted or substituted by one or more fluorine atoms. In the formulae of this specification the dotted line (''''') indicates a substituent in the α-configuration, i.e. below the plane of the ring, and the wedged line (_______W ) indicates a substituent in the β-configuration, i.e. above the plane of the ring. The configurations of the chiral centers in the side chain is unspecified; the invention is meant to include both the single "R" and "S" epimers as well as their "R S" mixtures. The invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) . It is known in the chemical literature that α-fluorinated ketones form stable gem-diols with water; so they are sometimes obtained as a mixture of a hydrate form and a ketone form, whose ratio depends on steric and electronic factors (Hudlicky H. , Chemistry of Organic fluorine compounds, 2nd edition, Ellis Horwood Ltd. ) : R-C-CF 2 -R 1 > R-C-CF 2 -R' ll « — / \ 0 H 2 0 OH OH ketone form hydrate form wherein R and R 1 are generic substituents. In this specification the α-fluorinated ketones are meant to include both these forms, i.e. they may exist in the pure ketone form or in the pure hydrate (ge - diol) form or as a mixture of both ketone and hydrate form. The invention includes also all the possible isomers of formula (I) and their mixtures. Also the metabolites and the metabolic precursors of the compounds of formula (I) are within the scope of the present invention. In this specification the alkyl groups and the aliphatic portions of the arylalkyl, cycloalkylalkyl and the heterocyclylalkyl groups may be straight or branched chain. A C,-C 4 alkyl group may be, for example, methyl, ethyl, isopropyl, n-butyl or tert-butyl. A C,-C 6 straight or branched alkylene chain may be, for example, a straight or branched C,-C 4 alkylene chain, in particular, -CH 2 -, -CH 2 -CH 2 -. A C,-C 6 alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl or iso- hexyl. The C,-C 6 alkyl group may be unsubstituted or substituted by one or more, preferably 3, 4, 5 or 6, fluorine atoms and may be, in particular, fluoromethyl, difluoromethyl, trifluoromethyl , 2 ,2 , 2-trifluoroethyl, 3 , 3 , 3-trifluoropropyl, 4,4,4-trifluorobutyl, 1-tri- fluoromethylethyl, 2-trifluoromethylprop-1-yl, penta- fluoroethyl, 1, 1, 1-3 , 3 , 3-hexafluoroprop-2-yl . or 4,4,5,5,5-pentafluoropentyl. A C,-C 4 alkoxycarbonyl group may be, for example, ethoxy-, ethoxy-, propoxy- or butoxycarbonyl, preferably methoxycarbonyl. A C,-C 4 alkoxy group may be, for example, methoxy, ethoxy, propoxy or butoxy, preferably methoxy. A di-(C,-C 4 -alkyl) amino may be, for example, dimethylamino. A C j -C 4 alkylthio group may be, for example, methylthio, ethylthio, propylthio, or butyl- thio, preferably methylthio or ethylthio. A C,-C 6 alkyl group substituted by one or more substituents other than fluorine may be, for example, CH 2 SH, CH 2 SCH 2 CH 3 , CH 2 CH 2 SCH 3 , CH 2 OH, CH 2 OCH 3 , CH(OH)CH 3 , CH(OCH 3 )CH 3 , CH 2 CONH 2 , CH 2 CH 2 CONH 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 CH 2 CH 2 CH 2 NH 2 , A C 5 -C 7 cycloalkyl may be, for example, cyclopentyl, cyclohexyl or cycloheptyl. A C 6 -C 10 cycloalkylalkyl group may be, for example, a (C 5 -C 7 cycloalkyl) alkyl, preferably (C 5 -C 7 cycloalkyl) methyl or (C 3 -C 7 cycloalkyl) ethyl, in particular, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl unsubstituted or substituted by one or more, preferably one, fluorine atoms, in particular, 1-fluoro-1-cyclo- hexylmethyl. An aryl group may be, for example, phenyl unsubstituted or substituted by one or more, preferably one, chloro, bromo, fluoro, C^C,, alkyl, preferably methyl, C,-C 4 alkoxy, preferably methoxy, hydroxy, or trifluoromethyl groups, in particular, 4-methylphenyl, 4-hydroxyphenyl, 4— ethoxyphenyl , 4-trifluoromethylp enyl, 4-f luorophenyl . A C 7 -C 10 arylalkyl group may be, for example, phenyl (C t -C 4 alkyl) , preferably benzyl, unsubstituted or ring substituted by one or more, preferably one or two, chloro, bromo, fluoro, C^C . , alkoxy preferably methoxy, hydroxy or trifluoromethyl groups, in particular 4-hydroxybenzyl, 4-methoxybenzyl, 4-hydroxy-3-methoxy- benzyl, 3 ,4-dimethoxybenzyl, 4-trifluoromethylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-fluoro-4-hydroxybenzyl. A C 6 -C 10 heterocyclylalkyl group may be, for example, heterocyclyl (C,-C 4 alkyl) , for example heterocyclyl- methyl, preferably imidazolyl-methyl or indolylmethyl, unsubstituted or ring substituted by one or more, preferably one, fluorine atoms, in particular, (4- i idazolyl) -methyl, (3-indolyl) -methyl, (5-fluoro- indolyl) -methyl, (6-fluoroindolyl)methyl or (3-imid- azolyl)methyl. In the above formula (I) CH, A is, preferably, a bond or -C IH-. R, is, preferably, hydrogen or methyl. R 2 is, preferably, the side-chain of the most common natural and unnatural uiv- no acids, optionally, substituted by one or more fluorine atoms. When R 2 is an unsubstituted C,-C 6 alkyl group, it is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl , sec-butyl , tert-butyl , n-pentyl , iso-pentyl , n-hexyl , iso-hexyl . When R 2 is a substituted C,-C 6 alkyl group , it is preferably -CH 2 F , -CHF 2 , CF 3 , CF 3 -CH 2 - , CF 3 -CH 2 -CH 2 - , CF 3 CF 3 CF 3 I I I CF 3 -CH 2 -CH 2 -CH 2 -, CH 3 -CH-, CH 3 -CH-CH 2 -, CF 3 -CH-, CF 3 -CF 2 -CH 2 -CH 2 -CH 2 -, CH 3 0-CH 2 -, CH 3 -S-CH 2 -CH 2 -. When R 2 is a C 5 -C 7 cycloalkyl, it is preferably cyclo- hexyl. When R 2 is a C 6 -C 10 cycloalkylalkyl, it is preferably cyclohexylmethyl. When R 2 is an aryl, it is preferably phenyl. When R 2 is a C 7 -C lt) arylalkyl, it is preferably benzyl. When R 2 is a heterocyclyl alkyl, it is preferably (3- imidazolyl) ethyl or (3-indolyl)methyl. R 3 is preferably hydrogen, methyl, ethyl, phenyl, benzyl. When Z is a C,-C 6 alkyl as defined above under a') , preferably it is methyl, ethyl, trifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, n-propyl, n-butyl, sec-butyl. When Z is a group OR 5 as defined above under b'), R, is preferably methyl, ethyl, t-butyl. When Z is a group -N as defined above under c') *7 preferably it is -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHCH(CH 3 ) 2 , - NHC(CH 3 ) 3 , -NHCH 2 C(CH 3 ) 3 , -N(C 2 H 5 ) 2 , -N[CH(CH 3 ) 2 ] 2 , -NH-/ > , NH-Ph, piperidyl, piperazinyl, morpholynyl. Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with pharmaceutically acceptable bases, either inorganic bases, such as, for example, alkali metal, e.g., sodium or potassium, or alkaline-earth metal, e.g., calcium or magnesium, or zinc or aluminium hydroxides, or organic bases such as, for instance, aliphatic amines as, e.g., methylamine, diethylamine, trimethylamine, ethylamine and heterocyclic amines, e.g., piperidine. A preferred class of compounds according to the invention are the compounds of formula (I) wherein: A is a single bond; R, is hydrogen or methyl; R 2 is methyl, iso-propyl, iso-butyl, sec-butyl, tert- butyl, trifluoromethyl, 1-trifluoromethyleth-1-yl, 2- trifluoromethylprop-1-yl, 2-methylthioeth-l-yl, methoxy- methyl, phenyl or benzyl; R 3 is hydrogen or methyl; Z is methyl, n-butyl, trifluoromethyl, pentafluoroethyl; or a group OR 5 wherein R 5 is methyl, ethyl or tert-butyl; or a group -N wherein each of ^, and R 7 is, \ independently, hydrogen, ethyl, isopropyl, neopentyl, provided that, when Z is a group OR 5 as defined hereinabove, R 2 is trifluoromethyl, 1-trifluoromethyl- eth-l-yl, 2-trifluoromethylprop-1-yl, 2-methylthioethyl, methoxymethyl. Examples of specific compounds preferred under this invention are: 1) 17β-[N- (2-oxobut-3-y1)carba oyl]androsta-3,5-diene- 3-carboxylic acid; 2) 17β-[N-(3-methyl-2-oxobut-3-yl)carbamoyl]androsta- 3 , 5-diene-3-carboxylic acid; 3) 17β-{ [N- (2-oxobut-3-yl)-N-methyl]carbamoyl}androsta -3 , 5-diene-3-carboxylic acid; 4) 17β-[N-(4-methyl-2-oxopent-3-yl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid; 5) 17β-[N-(l, 1, 1-trifluoro-2-oxobut-3-yl) carbamoyl] androsta-3 , 5-diene-3-carboxylic acid; 6) 17β-[N-(l, 1, 1-trifluoro-3-methyl-2-oxobut-3-yl) carbamoyl]androsta-3 , 5-diene-3-carboxylic acid; 7) 17β-{ [N- (1,1, 1-trifluoro-2-oxobut-3-yl) -N-methyl] carbamoyl}androsta-3,5-diene-3-carboxylic acid; 8) 17β-[N-(l, l,l-trifluoro-4-methyl-2-oxopent-3-yl) carbamoyl]androsta-3, 5-diene-3-carboxylic acid; 9) 17β-[N-(l,l,l,2, 2-pentafluoro-3-oxopent-4-yl) carbamoyl]androsta-3,5-diene-3-carboxylic acid; 10) 17β-[N-(l,l,l-trifluoro-3-phenyl-2-oxoprop-3-yl) carbamoyl]androsta-3 , 5-diene-3-carboxylic acid; and 11) 17β-[N-(l,l, l-trifluoro-3-benzy1-2-oxoprop-3-yl) carbamoyl]androsta-3, 5-diene-3-carboxylic acid. The above listed preferred compounds, according to their progressive number, are tabulated below, with reference to the substituents as defined for formula (I) : No. A R * R 2 R 3 Z 1 bond H CH 3 H CH 3 2 bond H CH 3 CH 3 CH 3 3 bond CH 3 CH, H CH 4 bond H iPr H CH 3 5 bond H CH 3 H CF 3 6 bond H CH 3 CH 3 CF 3 7 bond CH 3 CH 3 H CF 3 8 bond H iPr H CF 3 9 bond H CH 3 H CF 2 CF 3 10 bond H Ph H CF 11 bond H PhCH 2 H CF 3 The compounds of formula (I) or pharmaceutically acceptable salts thereof may be obtained by a process comprising: 1) hydrolysing a compound of formula (II) wherein R is a straight or branched C,-C 4 alkyl group, A, R,, R 2 , R 3 and Z are as defined above; or 2) oxidizing a compound of formula (III) wherein A, R,, R 2 , R 3 and Z are as defined above and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers. The hydrolysis of a compound of formula (II) according to the process variant 1) may be carried out, e.g., in a suitable solvent, such as, for example, methanol, ethanol, tetrahydrofurane, dioxane, in the presence of an aqueous concentrated solution of an alkali metal hydroxide such as, for example, potassium hydroxide, sodium hydroxide or, preferably, lithium hydroxide, for a time varying from some hours to some days, at a temperature ranging from about 0°C to the reflux temperature of the solvent, optionally under an inert atmosphere of nitrogen. The oxidation of a compound of formula (III) according to the process variant 2) may be carried out according to the Swern methodology, as described, e.g., in Synthesis 1981, 165. In particular, the oxidation may be carried out treating the compound dissolved in a solvent such as, for example, methylene chloride with dimethylsulphoxide and oxalyl chloride, at a temperature ranging from about -78°C to room temperature for a time varying from about 15 minutes to about 2 hours. When Z is a fluorinated alkyl group, particularly a CF 3 group, the oxidation may be fruitfully performed also with the Dess-Martin reagent, as reported, e.g., in Tetr.Lett. 1987, 2 . 8, 4259. Standard procedures may be used for converting a compound of formula (I) into a pharmaceutically acceptable salt thereof as well as for obtaining a free compound from the corresponding salt and for separating a mixture of isomers of formula (I) into the single isomers . A compound of formula (II) may be obtained by carbalkoxylation of a compound of formula (IV) wherein Tf is a trifluoromethansulphonyl group (CF 3 -S0 2 -) , W is a carbonyl group or a -CH- group wherein P is hydrogen or a suitable protecting group of the hydroxy function, R,, R 2 , R 3 and Z are as defined above, so obtaining, when W is a carbonyl group, a compound of formula (II) or, when W is a -CH- group, a compound of OP formula (V) wherein R, R,, R 2 , R, Z and P are defined above. A compound of formula (V) may then be transformed into a compound of formula (II) by removing the protecting group P of the hydroxy function, if it is present, and oxidizing. The carboxylation may be carried out, e.g., by treating a solution of the compound of formula (IV) in a suitable organic solvent, preferably dimethylformamide (DMF) , with an organic base such as, for example, triethylamine (TEA) , a palladium complex such as, for example, bis (triphenylphosphine) palladium (II) acetate or bis (triphenylphosphine) palladium (II) chloride, and a C,-C 4 alkyl alcohol. Optionally the palladium complexes, can ha formed in situ, by adding, separately, a phosphine, such as triphenylphosphine, and a palladium salt, such as, for example, palladium (II) acetate or palladium (II) chloride. Then the reaction mixture is purged with carbon monoxide (CO) for some minutes and then stirred under a CO balloon for a time varying from one hour to 48 hours, at a temperature ranging from 0°C to 40°C. Analogous procedure is described, e.g., in Tetr. Lett. 26 (8) , 1109-12, (1985) . A suitable protecting group of the hydroxy function may be, for example, a tetrahydropyranyl group or a silyl group, preferably trimethylsilyl or di ethyltertbutyl- εilyl. The removal of the protecting group of the hydroxy function in a compound of formula (V) may be achieved by the usual methods known in the art. The oxidation of a compound of formula (V) wherein P is hydrogen may be performed as described above for the oxidation of a compound of formula (III) according to the process variant 2) . A compound of formula (IV) may be obtained by reacting a compound of formula (VI) wherein A is as defined above with a compound of formula (VII) R 2 I R,-NH-C-W-Z (VII) R 3 wherein R,, R 2 , R 3 , W and Z are as defined above. A reaction between a compound of formula (VI) and a compound of formula (VII) , may be carried out, e.g., in an inert solvent such as, for example, CH 2 C1 2 , THF, AcOEt, DMF, benzene, at a temperature ranging from about 0°C to about 100°C, optionally in the presence of an organic base such as, for example, pyridine, p-dimethyl- aminopyridine or triethylamine, for a time varying from about one hour to about 5 days. The compounds of formula (VII) are often used as N-salt- derivatives, preferably hydrochlorides or trifluoro- acetates, and the free amino group is formed in situ in the presence of an organic base such as, for example, pyridine, or a tri-C,-C 6 -alkylamine, preferably triethyl¬ amine. The compound of formula (VI) are known compounds (European Patent Application 0465123 A2) . A compound of formula (VII) may be obtained by known methods as, for example, deprotecting a compound of formula (VIII) wherein R,, R 2 , R 3 and Z are as defined above and Y is an amino protecting group commonly used in the synthesis of α-aminoacids and peptides, such as, for example, N-benzoyl, N-benzyloxycarbonyl (Cbz) , N-tert-butoxy- carbonyl (BOC) , 2, 2 , 2-trichloroethoxycarbonyl (TClOC) , 2, 2 , 2-tribromoethoxycarbonyl (Tbcoc) , trifluoroacetyl (Tfac) . The reaction conditions for the deprotection depend on the amino protecting group used. For example, when Y is a BOC group, the reaction may be carried out in a solvent such as, for example, methylene chloride, chloroform or ethyl acetate, in the presence of a strong acid, e.g. hydrochloric acid or trifluoro- acetic acid, optionally in the presence of a tert-butyl cation scavenger such as thioanisole, at a temperature from about 0°C to about 40°C, for a time varying from half an hour to 24 hours. A compound of formula (VIII) wherein R,, R 2 , R 3 and Y are as defined above and Z is a group wherein * and R 7 are as defined above, may be obtained reacting a compound of formula (IX) wherein R,, R 2 , R 3 , Y are as defined above and X is an activating group of the carboxy function with a compound of formula (X) . X may be for example one of the following groups: For example, when X is the reaction may be carried out in a solvent such as methylene chloride, ethyl acetate or dimethylformamide, for a time varying from about half an hour to 24 hours, at a temperature ranging from about 0°C to the reflux temperature of the solvent. The compounds of formula (VIII) wherein R,, R 2 , R 3 and Y are as defined above and Z is a C,-C 6 alkyl group are known compounds; for example, they can be prepared starting from α-amino acids, according to the procedure reported in J.O.C. 4_8, 2260-2266 (1983) or to the Dakin- West reaction (J. Biol. Chem. 78 . , 91, 1928) . The compounds of formula (VIII) wherein R,, R 2 , R 3 are as defined above and Z is a OR, group are known. The compounds of formula (VIII) wherein R,, R 2 , R 3 and Y are as defined above and Z is a C,-C 6 alkyl group substituted by one or more fluorine atoms are known coi-.roi-.nJ-s or they can be obtained by known methods, for example, when Z is CF 3 the compounds may be obtained as reported in Tetr. Lett. 27(2) , 135-138 (1986) and Tetr. Lett. 27(14) , 1579-1582 (1986) . A compound of formula (IV) , wherein Tf is a trifluoro- methansulphonic group, W is a -CH- group, wherein P is OP a suitable protecting group of the hydroxy group, and A, R,, R 2 , R 3 and Z are as defined above, may be obtained from a compound of formula (XI) wherein W is a -CH- group, wherein P is a protecting OP group of the hydroxy function, and R,, R 2 , R 3 and Z are as defined above. The reaction may be carried out treating a solution of a compound of formula (XI) and an organic hindered base such as, for example, 2,6-ditertbutyl-4-methylpyridine, in a solvent such as, for example, methylene, chloride, with trifluoromethansulphonic anhydride, at a tempera¬ ture ranging for example from 0°C to about 50°C, for a time ranging from some minutes to about 3 hours, under an inert atmosphere of, for example, nitrogen. A compound of formula (XI) , wherein W is a group -CH-, OP wherein P is a protecting group of the hydroxy group, and A, R-, R 2 , R 3 and Z are as defined above, may be obtained by protection of a compound of formula (XI) , wherein W is a -CH- group and A, R,, R 2 , R 3 and Z are as OP defined above. Preferred protecting group for the hydroxy group of a compound of formula (XI) are, for example, tetrahydro- pyranyl or trimethylsilyl, and the protection is carried out in the usual conditions known in the art. A compound of formula (XI) , wherein W is a -CH- group, OP and A, R,, R 2 , R 3 and Z are as defined above, may be obtained by reaction of a compound of formula (XII) wherein X is an activating group of the carboxylic function, as defined for the compounds of formula (IX) and A is as defined above, with a compound of formula (VII) as defined above. A compound of formula (III) may be obtained hydrolyzing a compound of formula (V) wherein R is a straight or branched C,-C 4 alkyl group, P is hydrogen and R,, R 2 , R 3 and Z are as defined above. The hydrolysis of a compound of formula (V) may be carried out as reported for the hydrolysis of a compound of formula (II) according to the process variant 1) . The compounds of formula (I) of the present invention inhibit specifically the testosterone 5α-reductase enzyme and, therefore, are potent antiandrogens. For example,the inhibitory effect of the compounds of the invention on 5 -reductase was determined in vitro according to the procedure reported herebelow. In vitro assay of 5α-reductase inhibition. Inhibition of 5α.-reductase was evaluated using the particulate fraction from homogenates of hyperplastic human prostates as the enzyme source. The particulate fraction was prepared centrifuging prostate homogenate at 140,000 x g. The resulting pellet, washed several times, was resuspended in buffer and stored at -80°C in aliquots containing _____ 10 mg protein/ml. The assay for 5α-reductase was done in a final volume of 0.5 ml, in 40 itiM TRIS-HC1 buffer pH 5.5, containing 1 mM dithiothreitol , 5 mM NADPH, 1 μM [ 14 C]testosterone, an aliquot of the enzyme preparation and various concentrations of the inhibitors. After 30 in incubation at 37°C the reaction was terminated by addition of 2 ml cold diethyl ether and the organic phase was separated, evaporated under N 2 and resuspended in ethyl acetate. Testosterone metabolites in this extract were separated in TLC on silica gel F 254 plates (Merck) , using chloroform, acetone and n-hexane (2:1:2) as developing solvent system. Radioactivity on the plate was scanned and analysed from quantitative plots printed by a TLC-analyzer (Berthold) . The fractional 5α-reduction of testosterone was calculated by relating the 14 C-radioactivity in the 5α- reduced metabolites (5α-dihydrotestosterone, 3α- and 3β- androstanediols) regions to the total radioactivity in the testosterone and Sen-reduced metabolites regions. The concentration of each compound required to reduce control 5 -reductase activity by 50% (IC 50 ) was determined by plotting % inhibition versus log of inhibitor concentration. In view of the activity shown in the above test procedure, the compounds of the invention can be therapeutically useful in the situations in which a decrease in androgen action, by means of 5α-reductase inhibition, is desirable such as, for example, benign prostatic hyperplasia, prostatic and breast cancers and certain skin-air conditions such as, e.g., acne, seborrhoea, female hirsutism and male pattern baldness. A mammal, e.g., a human or animal, may thus be treated by a method which comprises administering thereto a pharmaceutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as defined above. The toxicity of the compounds of the invention is quite negligible so that they can be safely used in therapy. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g., intra-muscularly, or by intravenous injection or infusion; or topically, e.g., in the form of creams. The dosage depends on the age, weight, conditions of the patient and administration route; for example, the dosage adopted for oral administration to adult humans may range from about 1 to 200 mg pro dose, from 1 to 3 times daily. As already said, the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent) . The pharmaceutical compositions containing the compounds of the invention are usually prepared following con¬ ventional methods and are administered in a pharma¬ ceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agents, e.g., a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dye-stuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyl¬ cellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycol, e.g., propylene glycol and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g., cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. Conventional carriers may be used for topical formulations. The present invention further provides a compound of formula (I) , or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy in particular for use as a testosterone α-reductase inhibitor. The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a testosterone 5o:-reductase inhibitor. The following Examples further illustrate the invention. The reported NMR data are determined in CDC1 3 . The abbreviations THF, DMF, DDQ used in the present specification stand, respectively, for tetrahydrofuran, dimethylformamide and 2, 3-dichloro-5, 6-dicyanobenzo- quinone. The nomenclature used to identify the compounds in the following examples, refers to a numbering of the skeleton as shown herebelow: -Z Example 1 (22RS) -17β-[N-(1,1, 1-trifluoro-2-oxobut-3-yl) carbamoyl] androsta-3, 5-diene-3-carboxylic acid [Compound (I): A=bond, R=H, R,=H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] . A mixture of methyl (22RS) -17β-[N- (1, 1, 1-trifluoro-2- oxobut-3-yl) carbamoyl]androsta-3, 5-diene-3-carboxylate [Compound (II) : A=bond, R=CH 3 , R,=H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] (160 mg) , methanol (6.6 ml) and aqueous lithium hydroxide (70 mg in 1.6 ml of water) is stirred at room temperature for 7 days. The methanol is evaporated under vacuum and water is added; the mixture is acidified with IN HC1 and extracted with methylene chloride; the organic layers are washed with brine, with water until neutrality, anhydrified over sodium sulphate and the solvent removed under vacuum. The yellowish solid obtained is purified by flash chro atography on silica gel (eluant: ethyl acetate/n- hexane 50:50 to 70:50) so obtaining 118.0 mg of the title compound as a white solid (mp: 210-220°C dec.) as a mixture of the ketone and hydrate form (ratio 1:2) . Elemental analysis: Calculated for C 25 H 32 F 3 N0 2 H 2 0 C 61.84% H 7.06% N 2.88 found C 61.40% H 7.11% N 2.77% NMR (CDC1 3 ) <S: 12.10 (bs, 1H, COOH) , 8.35 (m, CONH, ketone form) , 7.35 and 7.18 (2d, CONH, hydrate form), 7.1-7.0 ( , C(OH) 2 ), 6.92 (s, 1H, H(4)) , 5.82 (m, 1H, H(6)), 4,59 (m, NH-CH(CH 3 )COCF 3 ketone form) , 4,11 (m, NHCH(CH 3 )COCF 3 hydrate form), 1,10 and 1.25 (2d, 3H, NH-CH(CH 3 )COCF 3 ) , 0.83 (s, 3H, Me(19)) , 0.60 and 0.57 (2s, 3H, Me(18) ) . Following an analogous procedure the compounds listed below can be prepared: 17β- [N- (2-oxobut-3-yl ) carbamoyl ] androsta-3 , 5 -diene-3 -carboxy lie acid; 17β-[N- (3-methyl-2-oxobut-3-yl ) carbamoyl ] androsta-3 , 5 -diene-3 - carboxylic acid; 17β-{ [N-(2-oxobut-3-yl )-N-methyl ] carbamoyl}androsta-3, 5-diene-3- carboxylic acid; 17β-[N-(4-methyl-2-oxopent-3-yl ) carbamoyl )androsta-3, 5-diene-3- carboxylic acid; 17β-[N-(1,1, 1-trifluoro-3-methyl-2-oxobut-3-yl)carbamoyl)androsta- 3, 5-diene-3-carboxylic acid; 17β-{ [N-(1,1,1-trifluoro-2-oxobut-3-yl)-N-methyl]carbamoyl}androsta- 3, 5-diene-3-carboxylic acid; 17β-[N-(1,1, 1-trifluoro-4-methy1-2-oxopent-3-yl)carbamoyl)androsta- 3, 5-diene-3-carboxylιc acid; 17β-[ -(1, 1, 1,2,2-pentafluoro-3-oxopent-4-yl)carbamoyl]androsta-3,5- diene-3-carboxylic acid; 17β-[N-(1, 1, 1-trifluoro-3-phenyl-2-oxoprop-3-yl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid and 17β-[N-(1, 1, 1-trifluoro-3-benεyl-2-oxoprop-3-yl)carbamoyl]androsta- 3,5-diene-3-carboxylιc acid. Example 2 Methyl (22RS)-17β-[N-(l,l, 1-trifluoro-2-oxobut-3-yl) carbamoyl]androsta-3 , 5-diene-3-carboxylate. [Compound (II) : A=bond, R=CH , R,=H, R 2 =CH,, R 3 =H 3 , Z=CF 3 ] . A solution of (22RS-23RS)methyl-17β-[N-(l, 1, 1-trifluoro- 2-hydroxybut-3-yl) carbamoyl] androsta-3 , 5-diene-3- carboxylate. [Compound (V) : A=bond, P=H, R=CH 3 , Rι=H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] (250 mg) in methylene chloride (2.4 ml) is added within 10 minutes to a stirred solution of oxalyl chloride (0.194 ml) and dimethylsulphoxide (0.351 ml) in methylene chloride (6.3 ml) prepared according to the usual procedure, at -15°C. The reaction mixture is maintained at this temperature for 30 minutes, triethyl¬ amine (0.359 ml) is added and then it is allowed to warm to room temperature and stirred for further 2.5 hours. Water is added, the organic phase is separated and the aqueous layer is extracted several times with ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and the solvent is removed under vacuum. Purification of the crude by flash chromatography on silica gel (eluant methylene chloride/acetone 95:5) affords 160 mg of the title compound, as a mixture of trifluorochetone and its hydrate form. NMR (CDC1 3 ) 5: 8.35 (m, CONH, ketone form), 7.35 and 7.18 (2d, CONH, hydrate form), 7.1-7.0 (m, C(OH) 2 ) , 6.92 (s, 1H, H(4)) , 5.82 (m, 1H, H(6)), 4.59 (m, NH-CH(CH 3 ) COCF 3 ketone form), 4.11 (m, NHCH(CH 3 ) COCF 3 hydrate form) , 3.75 (s, 3H, COOCH 3 ) , 1.10 and 1.25 (2d, 3H, NH-CH(CH 3 ) COCF 3 ) , 0.83 (s, 3H, Me(19)), 0.60 and 0.57 (2s, 3H, Me(18)) . . Following an analogous procedure the compounds listed below can be prepared: Methyl 17 β- ( N- ( 2 -oxobut- 3-yl ) carbamoyl ] androsta-3 , 5-diene-3- carboxylate ; Methyl 17β- [ N- ( 3-methyl-2-oxobut-3-yl ) carbamoyl ] androsta-3 , 5-diene- 3-carboxylate; Methyl 17β-{ [ N- ( 2-oxobut-3-yl ) -N-methyl ] carbamoyl } androsta-3 , 5- diene-3-carboxy late ; Methyl 17β- [ - ( 4-methyl-2-oxopent-3-yl ) carbamoyl ] androsta-3 , 5-diene- 3-carboxylate; Methyl 17β-[N-(l,l,l-trifluoro-3-methyl-2-oxobut-3-yl) carbamoyl] androsta-3, 5-diene-3-carboxylate; Methyl 17β- { [ N- ( 1 , 1 , 1-trif luoro-2-oxobut-3-yl ) -N-methyl ] carbamoyl } androsta-3, 5-diene-3-carboxylate; Methyl 17β-[N-( 1,1, 1-trif luoro-4-methyl-2-oxopent-3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate ; Methyl 17β-[N-(l, 1, 1, 2 , 2-pentaf luoro-3-oxopent-4-yl ) carbamoyl] androsta-3, 5-diene-3-carboxylate; Methyl 17β- [ N- ( 1 , 1 , 1-trif luoro-3-phenyl-2-oxoprop-3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate and Methyl 17β- [ - ( 1 , 1 , 1-trif luoro-3-benzyl-2-oxoprop-3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate . Example 3 (22RS) -17β- [N- (1,1, 1-trif luoro-2-oxobut-3-yl) carbamoyl ] androsta-3 , 5-diene-3-carboxylic acid [compound (I) A=bond, R=H, R,=H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] . A solution of (22RS-23RS)-17β-[N-(l,l,l-trifluoro-2- hydroxybut-3-yl) carbamoyl ]androstane-3 , 5-diene-3- carboxylic acid [Compound (III) . A=bond, R-=H, R 2 =CH 3 , R 3 =H, Z=CF 3 ] (140 mg) in methylene chloride (2.00 ml) is added, within 10 minutes, to a stirred solution of oxalyl chloride (0.114 ml) and dimethylsulphoxide (0.206 ml) in methylene chloride (3.70 ml) prepared according to the usual procedure, at -15°C. The reaction mixture is maintained at this temperature for 30 minutes, triethylamine (0.211 ml) is added and then it is allowed to warm to room temperature and stirred for further 2.5 hours. Water is added, the organic phase is separated and the aqueous layer is extracted several times with ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and the solvent is removed under vacuum. The crude is purified by flash chromatography (eluant ethyl acetate/n-hexane 70:50) so obtaining 80 mg of the title compound. NMR (CDC1 3 ) <S: 12.10 (bs, 1H, COOH) , 8.35 (m, CONH, ketone form) , 7.35 and 7.18 (2d, CONH, hydrate form), 7.1-7.0 (m, C(OH) 2 ) , 6.92 (s, 1H, H(4)) , 5.82 (m, 1H, H(6)) , 4.59 (m, NH-CH(CH 3 )COCF 3 ketone form) , 4.11 (m, NHCH(CH 3 )COCF 3 hydrate form) , l.io and 1.25 (2d, 3H, NH-CH(CH )COCF 3 ) , 0.83 (s, 3H, Me(19) ) , 0 . -, and 0.57 (2s,3H, Me(18)). Following an analogous pocedure the compounds listed below can be prepared: 17β- [N-(2-oxobut-3-yl )carbamoyl ]androsta-3, 5-diene-3-carboxylic acid; 17β-[N-(3-methyl-2-oxobut-3-yl ) carbamoyl ] androsta-3, 5-diene- 3- carboxylic acid; 17β-{ [N-(2-oxobut-3-yl ) -N-methyl ] carbamoyl } androsta-3 , 5 -diene-3 - carboxylic acid; 17β- [ N- ( 4-methyl-2-oxopent-3-yl ) carbamoyl ] androsta-3 , 5-diene-3- carboxylic acid; 17B-[N-(1, 1, 1-trifluoro-3-methyl-2-oxobut-3-yl)carbamoyl]androsta- 3, 5-diene-3-carboxylic acid; 17β-{[N-(l,l, 1-trifluoro-2-oxobut-3-y1 ) -N-methyl ] carbamoyl} androsta-3, 5-diene-3-carboxylic acid; 17β-[ -(1, 1, 1-trifluoro-4-methyl-2-oxopent-3-y1)carbamoyl] androsta- 3, 5-diene-3-carboxylic acid; 17β-[N-(1, 1, 1,2,2-pentafluoro-3-oxopent-4-yl)carbamoyl] androsta- 3,5-diene-3-carboxylic acid; 17β-[N-(1,1,1-trifluoro-3-phenyl-2-oxoprop-3-yl)carbamoyl] androsta- 3,5-diene-3-carboxylic acid and 17β-[N-(1, 1,1-trifluoro-3-benzyl-2-oxoprop-3-yl)carbamoyl] androsta- 3, 5-diene-3-carboxylic acid. Example 4 (22RS-23RS) -17β-[N-(l, 1, 1-trif luoro-2-hydroxybut-3-yl) carbamoyl] androsta-3 , 5-diene-3-carboxylicacid [Compound (III): A=bond, R,=H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] . A mixture of methyl (22RS-23RS) -17β-[N- (1, 1, 1-trif luoro- 2-hydroxybut-3-yl) carbamoyl] androsta-3, 5-diene-3- carboxylate [Compound (V) : A=bond, P=H, R=CH 3 , R^H, R 2 =CH 3 , R 3 =H 3 , Z=CF 3 ] (200 mg) , methanol (8.2 ml), and aqueous lithium hydroxide (87 mg in 2.1 ml of water) is stirred at room temperature for 5 days. The methanol is evaporated under vacuum and water is added; the mixture is acidified with IN HCl acid and extracted with methylene chloride; the organic layers are washed with brine, water, dried over sodium sulphate and the solvent is removed under vacuum. The yellowish solid is purified by flash chromatography on silica gel (eluant ethyl acetate/n-hexane 50:50 - 70:30) so obtaining 140 mg of the title compound as a white solid (m.p. 230-240°C, dec) . Elemental analysis: Calculated for C 25 H 34 F 3 N0 4 : C 63.95% H 7.30% N 2.98% found: C 63.76% H 7.47% N 2.70% NMR (CDC1 3 ) δ : 12.00 (bs, 1H, COOH) , 7.15 (s, 1H, H(4)), 5.86 (m, 1H, H(6)) , 4.80 (bm, 1H, OH) , 4.32 (m, 1H, NHCH(CH 3 )), 4.08 ( , 1H, CH(0H)CF 3 ) , 1.35 (d, 3H, NHCH(CH 3 )) , 0.93 (ε, 3H, Me(19)) , 0.73 (s, 3H, Me(18)) . Following an analogous procedure the compounds listed below can be prepared: 17β- [ N- ( 2-hydroxybut-3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylic acid; 17β- [ N- ( 3-methy 1-2 -hydroxybut-3-yl ) carbamoyl ] androsta-3 , 5-diene-3- carboxylic acid; 17β- { [ - ( 2-hydroxybut-3-yl ) -N-methyl ] carbamoyl }androsta-3 , 5-diene-3- carboxylic acid ; 17β- [ N- ( 4-methyl-2-hydroxypent-3-yl ) carbamoyl ] androsta-3 , 5-diene-3- carboxylic acid; 17β-[N-(l, 1, 1-trifluoro-3-methy1-2-hydroxybut-3-yl ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid; 17β-{ [N-(l, 1, 1-trifluoro-2-hydroxybut-3-yl)-N-methyl ]carbamoyl} androsta-3,5-diene-3-carboxylic acid; 17β-[N-(l, 1, 1-trifluoro-4-methy1-2-hydroxypent-3-yl ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid; 17β-[N-(l, 1,1,2, 2-pentafluoro-3-hydroxypent-4-y1 ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid; 17β-[N-(l, 1, 1-trifluoro-3-pheny1-2-hydroxyprop-3-yl) carbamoyl ] androsta-3,5-diene-3-carboxylic acid and 17β-[N-( 1, 1, 1-trifluoro-3-benzy1-2-hydroxyprop-3-yl ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid. Example 5 Methyl(22RS-23RS) -17β- [N- (1,1, 1-trif luoro-2-hydroxybut- 3-yl) carbamoyl] androsta-3 , 5-diene-3-carboxylate [Compound (V) : A=bond, R=CH 3 , R,=H, R 2 =CH 3 , R 3 =H 3 , P=H, Z=CF 3 ] . To a solution of (22RS-23RS) -N- (1 , 1 , 1-trif luoro-2- hydroxybut-3-yl) 3-{ [ (trif luoromethyl) sulphonyl ] oxy} androsta-3 , 5-diene-17β-carboxamide [Compound (IV) : A=bond, W=CHOH, Tf=CF 3 S0 2 , R.=H, R 2 =CH , R 3 =H 3 , Z=CF 3 ] . (1.70 g) in dimethylf ormamide (5.1 ml) , methanol (5.1 ml) and triethylamine (0.81 ml) , bis (triphenylphosphine) palladium (II) acetate (66.57 mg) is added. The mixture is purged with carbon monoxide for 5 minutes and then is stirred overnight at room temperature under a carbon monoxide atmosphere (maintained by means of a balloon) . Ethyl acetate is then added and the organic solution is washed with water until neutral, anhydrified over sodium sulphate and the solvent is removed under vacuum. The crude is purified by flash chromatography (eluant Ethyl acetate/n-hexane 30:70) so obtaining 1.52 g of the title compound as a white solid. NMR (CDC1 3 ) δ: 7.15 (s, 1H, H(4)), 5.86 (m, 1H, H(6)), 4.80 (bm, 1H, OH), 4.32 ( , 1H,NHCH(CH 3 )-) , 4.08 (m, 1H, CH(OH)CF 3 ), 3.75 (s, 3H, COOCH 3 ) , 1.35 (d, 3H, NHCH(CH 3 )-), 0.93 (s, 3H, Me(19)) , 0.73 (s, H, Me(18)) . Following an analogous procedure the compounds listed below can be prepared: Methyl 17β- [ N- ( 2-hydroxybut-3-yl ) carbamoyl ] androsta-3 , 5-diene-3- carboxylate; Methyl 17β-[N-(3-methyl-2-hydroxybut-3-yl)carbamoyl ]androsta-3, 5- diene-3-carboxylate; Methyl 17β-{ [ -(2-hydroxybut-3-y1)-N-methyl]carbamoyl}androsta-3,5- diene-3-carboxylate; Methyl 17β-[N-(4-methyl-2-hydroxypent-3-yl)carbamoyl]androsta-3, 5- diene-3-carboxylate; Methyl 17β-[N-(1,1,1-trifluoro-3-methyl-2-hydroxybut-3-yl)carbamoyl] androsta-3,5-diene-3-carboxylate; Methyl 17β-{[ N- ( 1 , 1 , 1-trifluoro-2-hydroxybut-3-yl)-N-methyl ] carbamoyl}androsta-3, 5-diene-3-carboxylate; Methyl 17β-[N- ( 1 , 1, 1-trifluoro-4-methy1-2-hydroxypent-3-yl ) carbamoyl]androsta-3, 5-diene-3-carboxylate; Methyl 17β- [ N- ( 1 , 1 , 1 , 2 , 2-pentaf luoro-3-hydroxypent-4-y 1 ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate; Methyl 17β-[N-(l,l, 1-trif luoro-3-pheny 1-2- hydroxy prop- 3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate and Methyl 17β- [ N- ( 1 , 1 , 1-trif luoro-3-benzyl-2-hydroxyprop-3-yl ) carbamoyl ] androsta-3 , 5-diene-3-carboxylate . Example 6 (22RS-23RS) N- (1, 1, l-trifluoro-2-hydroxybut-3-yl) 3- { [ (trifluoromethyl) sulphonyl]oxy}androsta-3, 5-diene-17β- carboxa ide [Compound (IV) : Tf=CF 3 S0 2 , A=bond, W=CHOH, R,=H, R 2 =CH 3 , R 3 =H, Z=CF 3 ] . To a stirred suspension of (2RS-3RS) -3-amino-l, 1, 1- trifluorobutan-2-ol hydrochloride (792.8 mg) in methylene chloride (60 ml) triethylamine (0.6 ml) is added; after 50 minutes S-2-pyridyl 3- { [ (trifluoromethyl) sulphonyl]oxy}androsta-3, 5-diene-17β- carbothioate [Compound (VI) : A=bond, Tf=CF 3 S0 2 ] (2.0 g) is added and the solution is stirred at room temperature for 60 hours. The solution is diluted with methylene chloride, washed with IN HC1 and dried over sodium sulphate. Purification of the crude by flash chromatography (eluant: n-hexane/ethyl acetate 80:20) affords 1.7 g of the title compound as a whitish solid. NMR (CDC1 3 ) δ : 5.95 (m, 1H, H(4)), 5.55 (m, 1H, NH) , 5.45 (m, 1H, H(6)), 4.65 (m, 1H, OH), 4.50-4.00 (m, 2H, NHCH (OH 3 ) CH (OH) CF 3 ) , 1.35 (d, 3H, NHCH(CH 3 )-) , 0.93 (s, 3H, Me(19)) , 0.68 (s, 3H, Me(18)) . Following an analogous procedure the compounds listed below can be prepared: N-(2-hydroxybut-3-yl) 3-{ [ (trif luoromethyl ) sulphonyl ]oxy} androsta- 3, 5-diene-17β-carboxamide; N-(3-methyl-2-hydroxybut-3-yl) -3-{[ (trif luoromethyl) sulphonyl ]oxy}- androsta-3, 5-diene-17β-carboxamide; N-(2-hydroxybut-3-yl)-N-methyl 3-{[ (trif luoromethyl ) sulphonyl ]oxy}androsta-3 , 5-diene-17β-carboxamide; N-(4-methyl-2-hydroxypent-3-yl) 3-{[ (trif luoromethyl) sulphonyl ]oxy} androsta-3, 5-diene-17β-carboxamide; N-( 1,1, 1-trif luoro-3-methyl-2-hydroxybut-3-yl) 3-{[ (trif luoromethyl) sulphonyl ]oxy} androsta-3, 5-diene-17β-carboxamide; N- ( 1 , 1 , 1-trif luoro-2-hydroxybut-3-yl ) -N-methyl 3-{ [ (trif luoromethyl ) sulphonyl ]oxy}androsta-3 , 5-diene-17β-carboxamide; N- ( 1 , 1, 1-trif luoro-4-methyl-2-hydroxypent-3-yl) 3-{ [ (trif luoro- methyl) sulphonyl ]oxy} androsta-3, 5-diene-17β-carboxamide; N- ( 1 , 1 , 1 , 2 , 2 -pent a f luoro-3-hydroxypent-4-yl ) 3-{ [ (trif luoro¬ methyl ) sulphonyl ]oxy} androsta-3, 5-diene-17β-carboxamide; N-(l, 1, 1,-trif luoro-3-pheny 1-2 -hydroxyprop-3-yl) 3-{ [ (trif luoro¬ methyl ) sulphonyl ]oxy}androsta-3 , 5-diene-17β-carboxamide; and N-(l, 1, 1,-trif luoro-3-benzy 1-2 -hydroxypr op- 3-yl ) 3-{ [ (trif luoro¬ methyl) sulphonyl ]oxy} androsta-3, 5-diene-17β-carboxamide. Example 7 Methyl(22RS-23RS)-17β-{N-[1,1, 1-trifluoro-2-hydroxybut- 3 -yl] carbamoyl] androsta-3, 5-diene-3-carboxylate [Compound (V) : A=bond, R=CH 3 , R,=H, R 2 =CH 3 , R 3 =H, P=H, Z=CF 3 ] . A solution of methyl(22RS-23RS) -17β-{N-[1, 1, 1-trifluoro- 2- (tetrahydropyran-2-yloxy) but-3-yl]carbamoyl}androsta- 3 , 5-diene-3-carboxylate [Compound (V) : A=bond, R=CH 3 , ml) is heated at 45°C for 5 hours. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate; the combined organic extracts are washed with saturated sodium bicarbonate, brine and dried over sodium sulphate. The solvent is removed under vacuum and the crude is purified by flash chromatography on silica gel (eluant ethyl acetate/n-hexane 80:20) so obtaining 356 mg of the solid compound. NMR (CDCl,) δ: 7.15 (s, 1H, H(4)) , 5.86 (m, 1H, H(6)) , 4.80 (bm, 1H, OH) , 4.32 (m, 1H, NHCH(CH 3 )-) , 4.08 (m, 1H, CH(OH)CF 3 ) , 3.75 (s, 3H, COOCH 3 ) , 1.35 (d, 3H, NHCH(CH 3 )) , 0.93 (ε, 3H, Me(19)), 0.73 (ε, 3H, Me(18) ) . Example 8 Methyl (22RS-23RS) -17β-{N-[l, 1, 1-trifluoro-2-(tetrahydro- pyran-2-yloxy) but-3-yl]carbamoyl}androsta-3, 5-diene-3- R*=*H, 1-trifluoro-2- (tetrahydropyran-2-yloxy)but-3-yl] 3-{ [ (trifluoromethyl) sulphonyl]oxy}androsta-3 , 5-diene-17β-carboxamide , methanol (1.60 ml) and triethylamine (0.25 ml) bis(tri- phenylphosphine) palladium (II) acetate (21.1 mg) is added. The mixture is purged with carbon monoxide for 5 minutes and then is stirred overnight at room temperature under a carbon monoxide atmosphere (maintained by means of a balloon) .- Ethyl acetate is then added and the organic solution is washed with water until neutral, anhydrified over sodium sulphate and the solvent is evaporated at reduced pressure. The crude is purified by flash chromatography (eluant: ethyl acetate/n-hexane 60:40) so obtaining 480 mg of the title compound. NMR (CDC1 3 ) δ : 7.15 (s, 1H, H(4)) , 6,45 (d, 1H, NH) , 5.86 (m, 1H, H(6)) , 4.55 (m, 1H, H(2')) , 4.19 (m, 1H, NHCH(CH 3 )-) , 4.03 ( , 1H, CH(OTHP)CF 3 ) , 3.95 and 3.55 (2m, 2H, CH 2 (6')) , 1,20 (d, 3H, NHCH(CH 3 )-) , 0.93 (s, 3H, Me(19)) , 0.73 (s, 3H, Me(18)) . Example 9 (22RS-23RS) N- [ 1 , 1 , 1-trif luoro-2- (tetrahydropyran-2- yloxy but- 3-yl] 3-{ [ (trif luoromethyl ) sulphonyl ] oxy} androsta-3 , 5-diene-17β-carboxamide. [Compound (IV) : To a solution of (22RS-23RS) N-[l, 1, 1-trif luoro-2- (tetrahydropyran-2-yloxy) but-3-yl] 3-oxo-androst-4-ene- 17β-carboxamide [Compound (XI) : A=bond, R,=H, R 2 =CH 3 , -CH- R 3 =H, = O- , Z=CF 3 ] (650 mg) and 2 , 6-di-tert-butyl- 4-methylpyridine (279 mg) in methylene chloride (60 ml) trifluoromethanesulphonic anhydride (0.249 ml) is added and the mixture is stirred for 30 minutes at room temperature. The mixture is then diluted with methylene chloride (6 ml) and filtered. The filtrate is washed with 5% hydrochloric acid (2x2 ml) , saturated sodium bicarbonate (2x2 ml) , brine, and dried over sodium sulphate. The solvent is evaporated under vacuum and the crude is purified by flash chromatography on silica gel (eluant ethyl acetate/n-hexane 70:30) to yield the title compound (575 mg) . NMR (CDC1 3 ) δ : 6.45 (d, 1H, NH) , 5.95 (m, 1H, H(4)) , 5.45 (m, 1H, H(6)), 4.55 (m, 1H, H(2')), 4.19 (m, 1H, NHCH(CH 3 )-) , 4.03 (m, 1H, CH(OTHP)CF 3 ) , 3.95 and 3.55 (2m, 2H, CH 2 (6')) , 1.20 (d, 3H, NHCH(CH 3 )) , 0.93 (s, 3H, Me (19)) , 0.68 (s, 3H, Me (18)) . Example 10 (22RS-23RS) N-[1, 1, 1-trifluoro-2- (tetrahydropyran-2- yloxy)but-3-yl]-3-oxo-androst-4-ene-17β- carboxamide [Compound (XI) : A=bond, R^H, R 2 =CH 3 , R 3 =H, To a solution of (22RS-23RS) N-(1, 1, 1-trifluoro-2- hydroxybut-3-yl) 3-oxo-androst-4-ene-17β-carboxamide [Compound (XI) : A=bond, R_=H , R 2 =CH 3 , R 3 =H, = ^CHOH, Z=CF 3 ] (840 mg) in methylene chloride (33 ml), 3,4- dihydro-2H-pyran (0.40 ml) and a catalytic amount of p- toluensulphonic acid (17 mg) are added and the solution is stirred at room temperature overnight. After diluting with methylene chloride the reaction mixture is washed with saturated sodium bicarbonate solution, with water until neutral, dried over sodium sulphate and the solvent is evaporated at reduced pressure. The crude oil is chromatographed on silica gel (eluant: n-hexane/ethyl acetate 50:50) to yield 650 mg of the title compound. NMR (CDC1 3 ) δ: 6.38 and 6.48 (2d, 1H, NH(21)), 5.73 (s, 1H, H(4)), 4.55 (m, 1H, H(2')) , 4.19 (m, 1H, NHCH(CH 3 )-CH(OTHP)CF 3 ) , 4.03 (m, 1H, NH-CH(CH 3 )-CH(OTHP)CF 3 ) , 3.95 and 3.55 (2m, 2H, CH 2 (6')), 1.20(d, 3H, NHCH(CH 3 )), 1.18 (s, 3H, Me(19)) , 0.87 and 0.85 (2s, 3H, Me(18) ) . Example 11 (22RS-23RS) N- ( 1 , 1, 1-trif luoro-2-hydroxybut-3-yl) 3-oxo- androst-4-ene-17β-carboxamide [Compound (XI) : A=bond, Rι=H, R 2 =CH 3 , R 3 =H, =^CH(OH), Z=CF 3 ] . To a stirred solution of (2RS-3RS) -3-amino-l, 1, 1- trif luorobutan-2-ol hydrochloride (525 mg) [Compound (VII) : R,=H, R 2 =CH 3 , R 3 =H, =CH(0H) , Z=CF ] in methylene chloride (30 ml) , triethylamine (0.39 ml) is added, at room temperature. After 30 minutes solid S-2-pyridyl 3-oxo-androst-4-ene-17β-carbothioate [Compound (XII) : A=bond ] (1.00 g) is added and the mixture is refluxed for 24 hours, After diluting with methylene chloride the reaction mixture is washed with IN hydrochloric acid, water until neutrality and dried over sodium sulphate. The solvent is removed under vacuum and the crude (1.1 g) is purified by flash chromatography (eluant: n-hexane /ethyl acetate 60:40) so obtaining 890 mg of solid (22RS-23RS) N- (1, 1, 1-trifluoro-2-hydroxybut-3-yl) 3-oxo- androεta-4-ene-17β-carboxamide. Example 12 Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets) 17β-[N-(l, l, 1-trifluoro-2-oxobut-3-yl) carbamoyl ] androsta-3 , 5-diene-3-carboxylic acid 2500 g corn starch 275 g talc powder 187 g calcium stearate 38 g The active substance was granulated with a 4% w/v aqueous solution of methyl cellulose. To the dried granules a mixture of the remainder of the ingredients is added and the final mixture compressed ir ' : ^ tablets of proper weight. Example 13 Two-piece hard gelatin capsules for oral use, each containing 250 mg of active substance were manufactured as follows. Compositions for 10,000 capsules 17β-[N-(l, 1, l-trifluoro-2-oxobut-3-yl) carbamoyl ] androsta-3 , 5-diene-3-carboxylic acid 2500 g lactoεe 1000 g corn starch 300 g talc powder 65 g calcium stearate 35 g The active substance was mixed with the starch-lactose mixture followed by the talc and calcium stearate.

Claims: CLAIMS 1) A compound of formula (I) wherein A is a single bond or a straight or branched C,-C 6 alkylene chain; R, is a hydrogen atom or a C,-C 6 alkyl group optionally substituted by one or more fluorine atoms; R 2 is: a) a C,-C 6 alkyl group optionally substituted by one or more substituents chosen among fluoro, C,-C 4 alkoxycarbonyl, carbamoyl, carboxy, hydroxy, C,-C 4 alkoxy, amino, di-C,-C 4 alkylamino, mercapto and C,-C 4 alkylthio; or b) a C 5 -C 7 cycloalkyl or a C 6 -C 10 cycloalkylalkyl group optionally substituted by one or more fluorine atoms; or c) an aryl or a C 7 -C l0 arylalkyl group, either unsubstituted or ring substituted by one or more substituents chosen among halogen, C,-C 4 alkyl, C,-C 4 alkoxy, hydroxy and trifluoromethyl; or d) a C 6 -C 1(l heterocyclylalkyl group in which the heterocyclic ring contains one or more hetero- atoms chosen among N, 0 and S and is either unsubstituted or ring sustituted by one or more fluorine atoms; R 3 is hydrogen, a C,-C 4 alkyl group or an aryl or a C 7 -C 10 arylalkyl group, either unsubstituted or ring substituted by one or more subεtituentε chosen among halogen, C,-C 4 alkyl, C,-C 4 alkoxy, hydroxy and trifluoromethyl; Z is: a') a C,-C 6 alkyl group optionally substituted by one or more fluorine atoms; b') an -0R S group wherein R 5 is a C,-C 6 alkyl group; C) group wherein each of R 6 and R 7 , in- dependently, is hydrogen, C,-C 6 alkyl, C 5 -C 7 cycloalkyl, phenyl, or R 6 and R 7 , taken together with the nitrogen to which they are linked, form a pentatomic or hexatomic saturated heteromonocyclic ring, optionally containing at least one additional heteroatom selected from oxygen and nitrogen; provided that when Z is a group 0R 5 as defined above under b') R 2 is a) a C,-C 6 alkyl group substituted by one or more substituents chosen among fluoro, C,-C 4 alkoxycarbonyl, carbamoyl, carboxy, C,-C 4 alkoxy, amino, di-C,-C 4 alkyl- a ino, mercapto and C,-C 4 alkylthio or b) a C,-C 7 cycloalkyl or a C 6 -C, 0 cycloalkylalkyl group, unsubstituted or substituted by one or more fluorine atoms or a pharmaceutically acceptable salts thereof. 2) A compound of formula (I) according to claim 1, wherein: A is a single bond; R, is hydrogen or methyl; R 2 is methyl, iso-propyl, iso-butyl, sec-butyl, tert- butyl, trifluoromethyl, 1-trifluoromethyleth-1-yl, 2-trifluoromethylprop-1-yl, 2-methylthioeth-l-yl, methcxymethyl, phenyl or benzyl; R 3 is hydrogen or methyl; Z is methyl, n-butyl, trifluoromethyl, pentafluoro¬ ethyl; or a group OR 5 wherein R s is methyl, ethyl or tert-butyl; or a group wherein each of R 6 and R 7 is, independently, hydrogen, ethyl, isopropyl , neopenthyl ; provided that, when Z is a group 0R as defined in claim 1 , R 2 is trif luoro¬ methyl , 1-trif luoromethyleth-1-yl , 2-trif luoro- methylprop-1-yl , 2-methylthioethyl , methoxymethyl , or a pharmaceutically acceptable salt thereof . ) A compound selected from the group consisting of : 17β- [ N- ( 2-oxobut-3-y 1 ) carbamoyl ] androsta-3 , 5-diene-3-carboxylic acid; 17β-[N-(3-methyl-2-oxobut-3-yl)carbamoyl]androsta-3,5-diene-3- carboxylic acid; 17β-{ [N-(2-oxobut-3-yl)-N-methyl]carbamoyl}androsta-3,5-diene-3- carboxylic acid; 17β-(N-(4-methyl-2-oxopent-3-yl)carbamoyl]androsta-3,5-diene-3- carboxylic acid; 17β-[N-( 1, 1, 1-trifluoro-2-oxobut-3-yl)carbamoyl]androsta-3,5- diene-3-carboxylic acid; 17β-(N-(l,l, 1-trifluoro-3-methyl-2-oxobut-3-yl ) carbamoyl] androsta-3, 5-diene-3-carboxylic acid; 17β-{[N-(l,l, 1-trifluoro-2-oxobut-3-yl)-N-methyl]carbamoyl} androsta-3, 5-diene-3-carboxylic acid; 17β-[N-( 1,1, 1-trifluoro-4-methy1-2-oxopent-3-yl ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid; 17β-[N-( 1, 1, 1,2,2-pentafluoro-3-oxopent-4-yl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid; 17β-[N-(l,l, 1-trifluoro-3-phenyl-2-oxoprop-3-y1 ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid and 17β-[N-( 1, 1, 1-trifluoro-3-benzyl-2-oxoprop-3-yl ) carbamoyl ] androsta-3, 5-diene-3-carboxylic acid, and the pharmaceutically acceptable salts thereof. 4) A process for preparing a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, the process comprising: 1) hydrolysing a compound of formula (II) wherein R is a straight or branched C,-C 4 alkyl group, A, R,, R 2 , R 3 and Z are as defined in claim 1; or 2) oxidizing a compound of formula (III) wherein A, R,, R 2 , R 3 and Z are as defined in claim 1 and, if desired converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or if desired separating a mixture of isomers of formula (I) into the single isomers. 5) A pharmaceutical composition comprising a pharma¬ ceutically acceptable carrier and/or diluent and, as an active principle, a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof. 6) A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. 7) A compound or salt according to claim 6 for use as a testosterone 5 -reductase inhibitor. 8) Use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as a testosterone 5 -reductase inhibitor. 9) A process for the preparation of a 17β-substituted androsta-3 , 5-diene carboxylic acid, or a pharma¬ ceutically acceptable salt thereof, the process being substantially as hereinbefore described in any one of Examples 1 to 3. 10) A pharmaceutically composition substantially as hereinbefore described in Example 12 or 13.

Inventors: DI SALLE ENRICO, NESI MARCELLA, PANZERI ACHILLE, DI SALLE, ENRICO, NESI, MARCELLA, PANZERI, ACHILLE
Applicants: PHARMACIA SPA, PHARMACIA S.P.A.
Application year: 1994
Main classification: C07J41
IPC codes: A61K31, A61P43, C07J41